Prostate cancer is currently the second leading cancer death in American men. Prostate cancer is dependent on androgen acting through the androgen receptor (AR) for growth and survival, and androgen ablation has been used for treatment of prostate cancer. Despite an initially favorable response, hormone ablation therapy eventually fails and the cancer progresses to an incurable metastatic disease. Epidemiological data regarding prostate cancer genetics indicate roles of AR mutation, as well as AR poly-glutamine (poly-Q) polymorphism, in susceptibility to prostate cancer development and response to therapy. The overall objective of this proposal is to create mouse prostate cancer models for studying the role of the AR in prostatic cancer development and metastasis. Using the Cre-loxP conditional gene knockout technology, several derivatives of TRAMP or PTEN-deficient mouse prostate cancer models with cell type-specific AR knockout (ARKO) (post-puberty epithelial, fibroblast-, and smooth muscle cell-specific ARKO), replacement of prostatic epithelial AR with AR(T857A) [murine equivalent of human AR(T877A)] mutant will be generated for in vivo study of the roles of the AR in prostate stromal cells or epithelial cells, the AR(T877A) mutation in prostate cancer initiation, progression, or metastasis. Prostate tumor initiation, progression, and/or metastasis in these models will be examined and compared with their littermates expressing wild type AR through histological analyses, immunohistochemical determination of various cellular markers, biochemical determination of the expression levels of tumor metastasis related genes and proteins, and analysis of invasive properties of their metastatic tumor. Through the differences in these parameters between the various ARKO or AR (T857A) mice and their wild type littermates, the role of the AR in each specific cell type and the AR(T877A) mutation in prostate carcinogenesis will be delineated. Information obtained from these studies not only will provide better understanding of the roles of the AR in prostate carcinogenesis, but also will be useful for designing new treatment regimen for prostate cancer in hormone refractory state. In addition, these models may be useful for testing new drugs for prostate cancer therapy. Project Narrative: New Mice Models for Studies of Androgen Receptor in Prostate Cancer We will generate various mouse models that lack the androgen receptor in individual cells of the prostate and study their influence on prostate cancer progression. Information obtained from our studies of the differences between these mice models will lead to our understanding some roles of the androgen receptor in the development of prostate cancer and also will be useful for designing new treatments for prostate cancer. In addition, these mice models may be useful for testing new drugs and treatments for prostate cancer therapy, which might eventually be used in humans.